PIASxα Ligase Enhances SUMO1 Modification of PTEN Protein as a SUMO E3 Ligase
PIASxα Ligase Enhances SUMO1 Modification of PTEN Protein as a SUMO E3 Ligase
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PIASx α 连接酶作为 SUMO E3 连接酶增强 PTEN 蛋白的 SUMO1 修饰
DOI：
10.1074/jbc.m113.508515
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发表时间：
2014-02-07
影响因子：
4.8
通讯作者：
Zhang, Xiaowei
中科院分区：
文献类型：
--
作者：
Wang, Weibin;Chen, Yifan;Zhang, Xiaowei
背景：PTEN肿瘤抑制因子的活性受到严格控制。结果：PIASx增强的PTEN SUMO化可调节PTEN活性。结论：PIASx是一种新的促进PTEN SUMO化的SUMO E3连接酶。重要性：PIASx介导的抑癌基因PTEN的SUMO化在肿瘤抑制中起着重要作用，其在细胞生存、细胞周期、增殖和凋亡等多个细胞过程中起着重要的调节作用。PTEN在各种人类癌细胞中经常突变或缺失以促进肿瘤发生。PTEN受SUMO化调控，但参与PTEN SUMO化的SUMO E3连接酶仍不清楚。在这里，我们证明了PIASx是PTEN的SUMO E3连接酶。PIASx在体外和体内与PTEN物理相互作用。它们的相互作用依赖于磷酸酶和PTEN的C2结构域以及PIASx的包含残基134 - 347的区域的完整性。PIASx通过减少PTEN泛素化增强了PTEN蛋白的稳定性，而PTEN SUMO 1缀合位点的突变中和了PIASx对PTEN蛋白半衰期的影响。在功能上，PIASx作为潜在的肿瘤抑制剂，通过稳定PTEN蛋白负调控PI3K-Akt通路。PIASx的过表达导致G（0）/G（1）细胞周期停滞，从而触发细胞增殖抑制和肿瘤抑制，而PIASx的敲除或催化活性的缺陷消除了这种抑制。总之，我们的研究表明PIASx是一种新的针对PTEN的SUMO E3连接酶，并且它在肿瘤抑制中正向调节PTEN蛋白水平。
Background: The activity of PTEN tumor suppressor is tightly controlled. Results: SUMOylation of PTEN enhanced by PIASx regulates PTEN activity. Conclusion: PIASx is a novel SUMO E3 ligase to promote SUMOylation of PTEN. Significance: PIASx-mediated SUMOylation of PTEN has a central role in tumor inhibition.The tumor suppressor PTEN plays a critical role in the regulation of multiple cellular processes that include survival, cell cycle, proliferation, and apoptosis. PTEN is frequently mutated or deleted in various human cancer cells to promote tumorigenesis. PTEN is regulated by SUMOylation, but the SUMO E3 ligase involved in the SUMOylation of PTEN remains unclear. Here, we demonstrated that PIASx is a SUMO E3 ligase for PTEN. PIASx physically interacted with PTEN both in vitro and in vivo. Their interaction depended on the integrity of phosphatase and C2 domains of PTEN and the region of PIASx comprising residues 134-347. PIASx enhanced PTEN protein stability by reducing PTEN ubiquitination, whereas the mutation of PTEN SUMO1 conjugation sites neutralized the effect of PIASx on PTEN protein half-life. Functionally, PIASx, as a potential tumor suppressor, negatively regulated the PI3K-Akt pathway through stabilizing PTEN protein. Overexpression of PIASx led to G(0)/G(1) cell cycle arrest, thus triggering cell proliferation inhibition and tumor suppression, whereas PIASx knockdown or deficiency in catalytic activity abolished the inhibition. Together our studies suggest that PIASx is a novel SUMO E3 ligase for PTEN, and it positively regulates PTEN protein level in tumor suppression.